(Oxazolin-4-yl) oxirane derivative

ABSTRACT

An (oxazolin-4-yl)oxirane derivative of formula [IX]                   
     wherein R 4  is an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl or an optionally substituted heteroarylalkyl, an enantiomer thereof or a salt thereof.

This application is a divisional of Ser. No. 09/580,831 filed May 30,2000, now issued as a U.S. Pat. No. 6,252,085 which is a divisional ofSer. No. 09/043,668 filed Apr. 14, 1998, now issued as U.S. Pat. No.6,133,461, which is the U.S. national stage of PCT/JP96/02756, filedSep. 24, 1996.

TECHNICAL FIELD

The present invention relates to a novel method for producing a of theformula [XVI]

wherein Me is methyl, Bu-t is t-butyl and Ph is phenyl, which is usefulas a treatment drug of HIV-related diseases based on its inhibitoryaction on proteases derived from viruses, various novel intermediatesuseful for producing said compound [XVI], and to the method forproduction of the intermediates. These intermediates can be used for notonly production of the above-mentioned compound [XVI] but also forproduction of various compounds.

BACKGROUND ART

The above-mentioned compound [XVI] useful as an HIV protease inhibitoris known as described in WO95/09843. This compound [XVI] has beenconventionally produced from serine as a starting material, byincreasing carbon and numerous other steps inclusive of stereoselectivereduction of carbonyl group. Such conventional production method isextremely complicated and inefficient, since it requires expensivestarting materials and constant low temperature conditions forreactions. Accordingly, there remain many problems to be solved beforethe conventional synthetic method is actually put to industrialpractice.

In addition, 2,2-dimethyl-6-amino-1,3-dioxepan-5-ol which is described,for example, in U.S. Pat. No. 4,439,613 is an intermediate for producinga compound useful as an X ray contrast medium, and even though thecompound obtained is a racemate, resolution of the racemate itself by amethod such as recrystallization has been extremely difficult. Moreover,this US patent does not suggest production of specific enantiomers ofthe present invention.

Accordingly, an object of the present invention is to provide a methodfor stereoselectively and extremely efficiently producing theabove-mentioned compound [XVI] useful as an HIV protease inhibitor uponsolution of the above-mentioned problems. Another object of the presentinvention is to provide a novel intermediate useful for producing saidcompound and a production method thereof.

DISCLOSURE OF THE INVENTION

The present inventors have made intensive studies in an attempt toachieve the above-mentioned objects, and found that a step comprisingacetalating or ketalating (z)-2-butene-1,4-diol, and epoxidation of theobtained compound to give a 3,5,8-trioxabicyclo[5. 1.0]octanederivative, which is followed by an epoxy ring-opening reaction using achiral amine, leads to a stereospecific (5R,6S)-6-substitutedamino-1,3-dioxepan-5-ol derivative or an enantiomer thereof, from whicha compound of the following formula [XV], that is, a compound inclusiveof the aforementioned compound [XVI] useful as an HIV proteaseinhibitor, can be extremely efficiently produced stereoselectivelythrough various other steps, which resulted in the completion of thepresent invention.

Thus, the present invention provides the following (1) to (15).

(1) A (5R,6S)-6-substituted amino-1,3-dioxepan-5-ol Derivative of theFormula [V]

wherein R¹ and R² are the same or different and each is a hydrogen atom,an alkyl or an aryl, or R¹ and R² combinedly form a cycloalkyl ringtogether with the adjacent carbon atom, and R³ is an aralkylamineresidue or amino acid derivative residue having an (R) or (S)configuration, an enantiomer thereof and a salt thereof.

(2) A Method for Producing a (5R,6S)-6-substitutedamino-1,3-dioxepan-5-ol Derivative of the Formula [V]

wherein R¹, R² and R³ are as defined above, and an enantiomer thereof,comprising subjecting a 3,5,8-trioxabicyclo[5.1.0]octane derivative ofthe formula [III]

wherein R¹ and R² are as defined above, to an epoxy ring-openingreaction using a chiral amine of the formula [IV]

R³—NH₂  [IV]

wherein R³ is as defined above, and crystallizing a produced mixture ofisomers.

(3) A (5R,6S)-6-amino-1,3-dioxepan-5-ol Derivative of the Formula [VI]

wherein R¹ and R² are as defined above, an enantiomer thereof and a saltthereof.

(4) A Method for Producing a (5R,6S)-6-amino-1,3-dioxepan-5-olDerivative of the Formula [VI]

wherein R¹ and R² are as defined above, an enantiomer thereof and a saltthereof, comprising subjecting a 3,5,8-trioxabicyclo[5.1.0]octanederivative of the formula [III]

Wherein R¹ and R² are as defined above, to an epoxy ring-openingreaction using a chiral amine of the formula [IV]

R³—NH₂  [IV]

wherein R³ is as defined above, and crystallizing a produced mixture ofisomers to give a (5R,6S)-6-substituted amino-1,3-dioxepan-5-olderivative of the formula [V]

wherein R¹, R² and R³ are as defined above, or an enantiomer thereof,and removing a substituent on an amino group of this compound to makethe 6-position thereof a non-substituted amino group.

(5) An Oxazoline Derivative of the Formula [X]

wherein R⁴ is an optionally substituted alkyl, an optionally substitutedaryl, an optionally substituted heteroaryl, an optionally substitutedaralkyl or an optionally substituted heteroarylalkyl, R⁵ is a hydrogenatom or an acyl, and Z is a substituent which functions as a leavinggroup together with an oxygen atom, an enantiomer thereof and a saltthereof.

(6) A Method for Producing an Oxazoline Derivative of the Formula [X]

wherein R⁴, R⁵ and Z are as defined above, and an enantiomer thereof,comprising treating a 1,3-dioxepane derivative of the formula [IX]

wherein R¹, R², R⁴ and Z are as defined above, or an enantiomer thereof,with a Lewis acid to form an oxazoline ring, followed by acylation asnecessary.

(7) A Method for Producing an Oxazoline Derivative of the Formula [X]

wherein R⁴, R⁵ and Z are as defined above, and an enantiomer thereof,comprising reacting a (5R,6S)-6-amino-1,3-dioxepan-5-ol derivative ofthe formula [VI]

wherein R¹ and R² are as defined above, an enantiomer thereof or a saltthereof, with a reactive carboxylic acid derivative having R⁴ wherein R⁴is as defined above, in the presence of a base, to give a(5R,6S)-6-acylamino-1,3-dioxepan-5-ol derivative of the formula [VIII]

wherein R¹, R² and R⁴ are as defined above, or an enantiomer thereof,reacting the resulting compound with a sulfonylating agent, treating theresulting compound with a Lewis acid, and acylating said compound, wherenecessary.

(8) An (oxazolin-4-yl)oxirane Derivative of the Formula [XI]

werein R⁴ is as defined above, an enantiomer thereof and a salt thereof.

(9) A Method for Producing an (oxazolin-4-yl)oxirane Derivative of theFormula [XI]

wherein R⁴ is as defined above, and an enantiomer thereof, comprisingtreating, with a base, an oxazoline derivative of the formula [X]

wherein R⁴, R⁵ and Z are as defined above, or an enantiomer thereof.

(10) A Method for Producing an (oxazolin-4-yl)oxirane Derivative of theFormula [XI]

wherein R⁴ is as defined above, and an enantiomer thereof, comprisingreacting a (5R,6S)-6-amino-1,3-dioxepan-5-ol derivative of the formula[VI]

wherein R¹ and R² are as defined above, an enantiomer thereof or a saltthereof, with a reactive carboxylic acid derivative having R⁴ wherein R⁴is as defined above, in the presence of a base, to give a(5R,6S)-6-acylamino-1,3-dioxepan-5-ol derivative of the formula [VIII]

wherein R¹, R² and R⁴ are as defined above, or an enantiomer thereof,reacting the resulting compound with a sulfonylating agent, treating theresulting compound with a Lewis acid, and acylating said compound, wherenecessary, to give an oxazoline derivative of the formula [X]

wherein R⁴, R⁵ and Z are as defined above, or an enantiomer thereof, andtreating the obtained compound with a base.

(11) A 4-(2-amino-1-hydroxyethyl)oxazoline Derivative of the Formula[XIII]

Wherein R⁴ is as defined above, and R⁶ and R⁷ are the same or differentand each is a hydrogen atom, an optionally substituted alkyl, anoptionally substituted aryl, an optionally substituted heteroaryl or anoptionally substituted aralkyl, or R⁶ and R⁷ combinedly form, togetherwith the adjacent nitrogen atom, a hetero ring, said hetero ring beingoptionally substituted by halogen atom, alkyl, alkenyl, alkoxy, amino,alkoxycarbonyl, carboxamide or alkyl-substituted carbamoyl, anenantiomer thereof and a salt thereof.

(12) A Method for Producing a 4-(2-amino-1-hydroxyethyl)oxazolineDerivative of the Formula [XIII]

wherein R⁴, R⁶ and R⁷ are as defined above, and an enantiomer thereof,comprising reacting an (oxazolin-4-yl)oxyrane derivative of the formula[XI]

wherein R⁴ is as defined above, or an enantiomer thereof, with an amineof the formula [XII]

wherein R⁶ and R⁷ are as defined above.

(13) A Method for Producing a 4-(2-amino-1-hydroxyethyl)oxazolineDerivative of the Formula [XIII]

wherein R⁴, R⁶ and R⁷ are as defined above, and an enantiomer thereof,comprising treating an oxazoline derivative of the formula [X]

wherein R⁴, R⁵ and Z are as defined above, or an enantiomer thereof witha base to give an (oxazolin-4-yl)oxyrane derivative of the formula [XI]

wherein R⁴ is as defined above, or an enantiomer thereof, and reactingthe resulting derivative [XI] with an amine of the formula [XII]

wherein R⁶ and R⁷ are as defined above.

(14) A Method for Producing an Amide Derivative of the Formula [XV]

wherein R⁴, R⁶ and R⁷ are as defined above, and R⁸ is a hydrogen atom,an alkyl, an optionally substituted aryl or an optionally substitutedaralkyl, and an enantiomer thereof, comprising subjecting a4-(2-amino-1-hydroxyethyl)oxazoline derivative of the formula [XIII]

wherein R⁴, R⁶ and R⁷ are as defined above, or an enantiomer thereof toring opening with a mercaptane of the formula [XIV]

 R⁸—SH  [XIV]

wherein R⁸ is as defined above.

(15) A Method for Producing an Amide Derivative of the Formula [XV]

wherein R⁴, R⁶, R⁷ and R⁸ are as defined above, and an enantiomerthereof, comprising reacting an (oxazolin-4-yl)oxirane derivative of theformula [XI]

wherein R4 is as defined above, or an enantiomer thereof, with an amineof the formula [XII]

wherein R⁶ and R⁷ are as defined above, to give a4-(2-amino-1-hydroxyethyl)oxazoline derivative of the formula [XIII]

wherein R^(4,) R⁶ and R⁷ are as defined above, or an enantiomer thereof,and subjecting this compound to ring opening with a mercaptane of theformula [XIV]

R⁸—SH  [XIV]

wherein R⁸ is as defined above.

As used herein, alkyl may be linear or branched and preferably has 1 to6 carbon atom(s). Specific examples thereof include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl,neopentyl, t-pentyl, hexyl, isohexyl, neohexyl, and the like. Morepreferred are lower alkyl having 1 to 4 carbon atom(s) such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl.

The optionally substituted alkyl includes, for example, theabove-mentioned alkyl which may be substituted by one or moresubstituent(s) which do(es) not influence the reaction. Examples of thesubstituents include hydroxy; halogen atoms such as fluorine, chlorine,bromine and iodine; amino; nitro; mono- or dialkylamino having 1 to 6carbon atom(s) such as methylamino, ethylamino, hexylamino,dimethylamino and diethylamino; cyano; cycloalkyl having 3 to 7 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl; alkoxy having 1 to 6 carbon atom(s) such as methoxy,ethoxy, propoxy, butoxy, pentyloxy and hexyloxy; carboxyl;alkoxycarbonyl having 2 to 6 carbon atoms such as methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and pentyloxycarbonyl;and the like. Preferred are hydroxy, halogen atom and amino.

The position and number of substituents on alkyl are not particularlylimited.

The cycloalkyl ring formed by R¹ and R² in combination together with theadjacent carbon atom is preferably cycloalkyl ring having 3 to 7 carbonatoms, which is exemplified by cyclopropyl ring, cyclobutyl ring,cyclopentyl ring, cyclohexyl ring, cycloheptyl ring, and the like.Preferred is that having 4 to 6 carbon atoms, such as cyclobutyl ring,cyclopentyl ring and cyclohexyl ring.

The chiral amine is that having an asymmetric carbon atom adjacent toamino group, that is, amine having an (R) or (S) configuration. Typicalexamples include aralkylamine, amino acid derivative and the like.

Examples of aralkylamine include (R)-1-phenylethylamine,(S)-1-phenylethylamine, (R)-1-(1-naphthyl)ethylamine,(S)-1-(1-naphthyl)ethylamine, (R)-α-phenylglycinol,(S)-α-phenylglycinol, and the like. Preferred is (R)-1-phenylethylamine.

The amino acid derivative includes, for example, amino acids having anasymmetric carbon atom adjacent to amino group, and derivatives thereof.Specific examples include amino acids such as (R)-serine, (S)-serine,(R)-α-phenylglycine and (S)-α-phenylglycine; amino acid derivatives suchas (R)-serine methyl ester, (S)-serine methyl ester, (R)-α-phenylglycinemethyl ester and (S)-α-phenylglycine methyl ester; and the like.Preferred is (R)-α-phenylglycine.

Aralkylamine residue and amino acid derivative residue respectively meana group which is other than amino group and which binds to amino groupin the above-mentioned aralkylamine and amino acid derivative.

Examples of aryl include phenyl, naphthyl, biphenyl, and the like.Preferred is phenyl.

The optionally substituted aryl includes, for example, theabove-mentioned aryl which may be substituted by one or moresubstituent(s) having no influence on the reaction. Examples of thesubstituent include those exemplified with respect to theabove-mentioned optionally substituted alkyl; alkyl having 1 to 6 carbonatom(s) such as methyl, ethyl, propyl, butyl, pentyl and hexyl; alkenylhaving 2 to 6 carbon atoms such as vinyl, allyl, butenyl, pentenyl andhexenyl; acyloxy having 2 to 6 carbon atoms such as acetyloxy,propionyloxy, butyryloxy, pivaloyloxy and hexanoyloxy; and the like.Preferred are alkyl, hydroxy, halogen atom, amino, nitro, alkoxy andacyloxy, and more preferred are alkyl, hydroxy, halogen atom, alkoxy andacyloxy.

While the position and number of substituents on aryl are notparticularly limited, preferred are compounds having 1 to 3substituent(s) and more preferred are compounds having 1 or 2substituent(s).

The aryl moiety of aralkyl is exemplified by those mentioned above suchas phenyl, naphthyl and biphenyl, and the alkyl moiety thereof isexemplified by those mentioned above having 1 to 6 carbon atom(s). Thearalkyl is exemplified by benzyl, phenethyl, phenylpropyl, phenylbutyl,phenylhexyl, and the like. Preferred is aralkyl comprising phenyl withC₁-C₄ alkyl.

The optionally substituted aralkyl is that which may be substituted byone or more substituent(s) which exert(s) no influence on the reaction.Examples of the substituent include those exemplified with respect tothe aforementioned optionally substituted aryl; haloalkyl having 1 to 6carbon atom(s) such as chloromethyl, chloroethyl and chlorobutyl; andthe like. Preferred are hydroxy, halogen atom, alkyl, alkoxy, haloalkyl,nitro, acyloxy, amino and cyano. More preferred are halogen atom, alkyl,alkoxy and acyloxy. Specific examples of optionally substituted aralkylinclude benzyl, halogen-substituted benzyl, alkyl-substituted benzyl,alkoxy-substituted benzyl, phenethyl, halogen-substituted phenethyl,alkyl-substituted phenethyl, alkoxy-substituted phenethyl, phenylpropyl,halogen-substituted phenylpropyl, alkyl-substituted phenylpropyl,alkoxy-substituted phenylpropyl, and the like. Preferred are benzyl,phenethyl, and the like.

While the position and number of substituents on aryl of theabove-mentioned aralkyl are not particularly limited, preferred arecompounds having 1 to 3 substituent(s).

Heteroaryl is, for example, pyridyl, pyrimidyl, pyrazinyl, furyl,thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, phthalazinyl,naphthyridinyl, quinazolinyl, cinnolinyl or quinoxalinyl, withpreference given to quinolyl and isoquinolyl.

The optionally substituted heteroaryl is that which may be substitutedby one or more substituent(s) which exert(s) no influence on thereaction. Examples of the substituent include those exemplified withrespect to the aforementioned optionally substituted aryl, and the like.Preferred are alkyl, hydroxy, halogen atom, amino, nitro, mono- ordialkylamino, alkoxy, acyloxy, carboxyl and alkoxycarbonyl. Morepreferred are alkyl, hydroxy, halogen atom, mono- or dialkylamino,alkoxy and acyloxy.

While the position and number of substituents on heteroaryl are notparticularly limited, preferred are compounds having 1 to 3substituent(s), and more preferred are compounds having 1 or 2substituent(s).

The heteroaryl moiety of the heteroarylalkyl includes, for example,those exemplified above and the alkyl moiety includes, for example,those exemplified above having 1 to 6 carbon atom(s). Specific examplesinclude 2-thienylmethyl, 3-furylmethyl, 4-pyridylmethyl,2-quinolylmethyl, 3-isoquinolylmethyl, and the like. Preferred is2-quinolylmethyl.

The optionally substituted heteroarylalkyl is, for example, that whichmay be substituted by one or more substituent(s) which exert(s) noinfluence on the reaction. Examples of the substituent include thoseexemplified with respect to the aforementioned optionally substitutedheteroaryl, and the like.

While the position and number of substituents on heteroaryl of theabove-mentioned heteroarylalkyl are not particularly limited, preferredare compounds having 1 to 3 substituent(s).

Examples of acyl include saturated aliphatic acyl preferably having 1 to18 carbon atom(s), such as formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, lauroyl, myristoyl,palmitoyl and stearoyl; unsaturated aliphatic acyl preferably having 3to 18 carbon atoms, such as acryloyl, propioloyl, methacryloyl,crotonoyl and oleoyl; aromatic acyl, such as benzoyl, naphthoyl,toluoyl, hydratropoyl, atropoyl and cinnamoyl; heterocyclic acyl, suchas furoyl, thenoyl, nicotinoyl and isonicotinoyl; acyl of hydroxy acidor alkoxylic acid, such as glycoloyl, lactoyl, glyceroyl, tropoyl,benziloyl, salicyloyl, anisoyl, vanilloyl, veratroyl, piperonyloyl,protocatechuoyl and galloyl; and the like. Preferred is saturatedaliphatic acyl and more preferred are formyl, acetyl, propionyl andbutyryl.

The hetero ring to be formed by R⁶ and R⁷ together with the adjacentnitrogen atom is, for example, saturated or unsaturated heteroarylhaving one or more nitrogen atom(s). Specific examples includeimidazolyl, triazolyl, tetrazolyl, pyrrolyl, pyrrolidinyl,imidazolidinyl, hydropyridyl, piperidino, piperazinyl, oxazinyl,morpholino, azepinyl, hydroazepinyl, indolyl, hydroindolyl, isoindolyl,hydroisoindolyl, hydroquinolyl, hydroisoquinolyl, and the like.Preferred are the groups represented by the following formulas

wherein the broken line may be either double bond or single bond, andmore preferred is the group represented by the following formula:

Said hetero ring may be substituted by halogen atom, alkyl having 1 to 6carbon atom(s), alkenyl having 2 to 6 carbon atoms, alkoxy having 1 to 6carbon atom(s), amino, alkoxycarbonyl having 2 to 6 carbon atoms,carboxamide, or alkyl-substituted carbamoyl wherein the alkyl moiety has1 to 6 carbon atom(s).

While the position and number of substituents on hetero ring are notparticularly limited, preferred are compounds having 1 to 3, morepreferably 1 or 2, substituent(s).

The halogen atom as the substituent for hetero ring includes, forexample, fluorine, chlorine, bromine and iodine.

The alkyl as the substituent for hetero ring includes, for example, theaforementioned ones having 1 to 6 carbon atom(s).

The alkenyl as the substituent for hetero ring includes, for example,linear or branched alkenyl preferably having 2 to 6 carbon atoms, whichis exemplified by vinyl, allyl, crotyl, 2-pentenyl, 3-pentenyl,2-hexenyl and 3-hexenyl. More preferred are those having 2 to 4 carbonatoms such as vinyl, allyl and crotyl.

The alkoxy as the substituent for hetero ring includes, for example,linear or branched alkoxy preferably having 1 to 6 carbon atom(s), whichis exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, s-butoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy,hexyloxy, and the like. More preferred are those having 1 to 4 carbonatom(s) such as methoxy, ethoxy, propoxy, isopropoxy and butoxy, withfurther preference given to those having 1 or 2 carbon atom(s) such asmethoxy and ethoxy.

The alkoxycarbonyl as the substituent for hetero ring includes, forexample, alkoxycarbonyl preferably having 2 to 6 carbon atoms, which isexemplified by the above-mentioned alkoxy having 1 to 5 carbon atom(s)with carbonyl group, and the like.

The alkyl-substituted carbamoyl as the substituent for hetero ringincludes, for example, those wherein the alkyl moiety preferably has 1to 6 carbon atom(s), which is exemplified by N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-t-butylcarbamoyl,N-pentylcarbamoyl, N-hexylcarbamoyl, and the like. Preferred isN-t-butylcarbamoyl.

The substituent (Z group) which functions as a leaving group togetherwith oxygen atom includes, for example, as a group joining with oxygenatom (leaving group: OZ group), sulfonic acid derivatives such astosyloxy (p-toluenesulfonyloxy), brosyloxy (p-bromobenzene-sulfonyloxy),mesyloxy (methanesulfonyloxy), benzenesulfonyloxy, camphorsulfonyloxyand trifyloxy (trifluoromethanesulfonyloxy). Preferred is mesyloxy(methanesulfonyloxy).

The reactive carboxylic acid derivative having R⁴ includes, for example,acid halides (e.g., R⁴COCl and R⁴COBr), acid anhydrides (e.g. (R⁴CO)₂O)and mixed acid anhydrides (e.g., R⁴COOCOt-Bu and R⁴COOCOOEt) ofcarboxylic acid having R⁴ (R⁴COOH). Preferred are acid halides and morepreferred is R⁴COCl.

Examples of Lewis acid include titanium chloride, tin chloride, zincchloride, zinc bromide, zinc iodide, magnesium chloride, titaniumalkoxide, boron bromide, boron chloride, boron fluoride, borontrifluoride-diethyl ether complex, aluminum chloride, aluminum bromide,thionyl chloride, phosphorus oxychloride, phosphorus chloride,trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyltrifluoromethanesulfonate, and the like. Preferred are thionyl chloride,tin chloride and boron trifluoride-diethyl ether complex, with morepreference given to boron trifluoride-diethyl ether complex.

Examples of salts include, but not limited to, alkali metal salts suchas sodium salt, potassium salt and cesium salt; alkaline earth metalsalts such as calcium salt and magnesium salt; organic amine salts suchas triethylamine salt, pyridine salt, picoline salt, ethanolamine salt,triethanolamine salt, dicyclohexylamine salt andN,N′-dibenzylethylenediamine salt; inorganic acid salts such ashydrochloride, hydrobromide, sulfate and phosphate; organic acid saltssuch as formate, acetate, trifluoroacetate, maleate and tartrate;sulfonates such as methanesulfonate, benzenesulfonate andp-toluenesulfonate; and amino acid salts such as arginine, aspartate andglutamate.

The present invention encompasses various isomers of respectivecompounds.

The method for producing compound [XV] from (z)-2-butene-1,4-diol whichis used as a starting compound, that is, the method for producingcompounds inclusive of the above-mentioned final objective compound[XVI] useful as an HIV protease inhibitor is described in detail in thefollowing.

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(7,) R⁸ and Z are as defined above,and X is halogen atom, alkoxycarbonyloxy, acyloxy or —OCOR⁴ wherein R⁴is as defined above.

Examples of halogen atom include those mentioned above.Alkoxycarbonyloxy preferably has 2 to 6 carbon atoms and is exemplifiedby methoxycarbonyloxy, ethoxycarbonyloxy, propoxy-carbonyloxy,butoxycarbonyloxy, and the like. Acyloxy preferably has 2 to 6 carbonatoms and is exemplified by acetyloxy, propionyloxy, valeryloxy,pivaloyloxy, and the like.

Step (1): Protection of Diol

The reaction per se is known wherein (z)-2-butene-1,4-diol [I] isreacted with an acetalating agent or a ketalating agent without solventor in a suitable solvent, in the presence of a dehydrating agent or asuitable catalyst such as acid, thereby to protect hydroxyl groups andproduce compound [II].

Examples of the acetalating agent and ketalating agent include carbonylcompounds such as formaldehyde, acetaldehyde, benzaldehyde, acetone,diethyl ketone, methyl ethyl ketone, acetophenone, cyclopentanone andcyclohexanone; gem-dialkoxy compounds such as dimethoxymethane,1,1-dimethoxyacetaldehyde, benzaldehydodimethyl-acetal,2,2-dimethoxypropane and cyclohexanone dimethylacetal; vinyl ethercompounds such as methyl vinyl ether, ethyl vinyl ether,2-methoxypropene, 2-ethoxypropene and 1-methoxycyclohexene; and thelike. Preferred are gem-dialkoxy compounds with more preference given to2,2-dimethoxypropane.

The catalyst is appropriately selected according to the kind ofacetalating agent and ketalating agent. Suitable catalyst includes, forexample, inorganic acids such as sulfuric acid, hydrochloric acid andnitric acid; and organic acids such as acetic acid, trifluoroaceticacid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acidand camphorsulfonic acid. Preferred are organic acids with morepreference given to p-toluenesulfonic acid.

Examples of the dehydrating agent include phosphorus pentoxide,molecular sieves, phosphorus pentachloride, and the like. Preferred aremolecular sieves.

The solvent is appropriately selected according to the kind ofacetalating agent and ketalating agent. Suitable solvent includes, forexample, hydrocarbon solvents such as benzene, toluene, hexane andxylene; ether solvents such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran and diglyme; halogen solvents such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solventssuch as ethyl acetate, methyl acetate and butyl acetate; and polarsolvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrileand acetone, with preference given to hydrocarbon solvents and morepreference given to a reaction without solvent.

The reaction (refluxing) temperature is suitably 0-200° C., preferably80-160° C.

The compound [II] can be used directly in the next step withoutisolation.

Step (2): Epoxidation with Oxidizing Agent

This step comprises epoxidation of compound [II] without solvent or in asuitable solvent using an oxidizing agent to give compound [III]. LikeStep (1), this reaction per se is known (see U.S. Pat. No. 4,439,613).

As the oxidizing agent, inorganic oxidizing agents such as hydrogenperoxide, Oxon (trademark); and organic oxidizing agents such asmetachloroperbenzoic acid, peracetic acid and t-butylhydro-peroxide canbe used. Preferred are inorganic oxidizing agents and more preferred ishydrogen peroxide. In this case, sodium hydroxide, or sodium hydroxideand disodium hydrogenphosphate in combination are desirably co-used forsmooth progress of the reaction.

The solvent is appropriately selected according to the kind of oxidizingagent. Suitable solvents include, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,acetonitrile, acetone, formic acid, acetic acid and water; and mixedsolvents thereof. Preferred are alcohol solvents and more preferred is amixed solvent of methanol, acetonitrile and water.

While the reaction temperature varies depending on the oxidizingconditions, it is suitably 0-150° C. and preferably 50-100° C. Thereaction time is preferably 3 to 8 hours.

The compound [III] can be used directly in the next step withoutisolation.

Step (3): Epoxy Ring-opening Reaction with Chiral Amine

This step comprises epoxy ring-opening of compound [III] with chiralamine [IV] of the formula: R³—NH₂ wherein R³ is as defined above, in asuitable solvent or without solvent, and subjecting the mixture ofisomers thus produced to crystallization (e.g. recrystallization) togive an optically pure compound [V] or an enantiomer thereof.

As mentioned above, the chiral amine includes, for example,aralkylamines represented by (R)-1-phenylethylamine,(S)-1-phenylethylamine, (R)-1-(1-naphthyl)ethylamine,(S)-1-(1-naphthyl)ethylamine, (R)-α-phenylglycinol and(S)-α-phenylglycinol; amino acids such as (R)-serine, (S)-serine,(R)-α-phenylglycine and (S)-α-phenylglycine; and amino acid derivativessuch as (R)-serine methyl ester, (S)-serine methyl ester,(R)-α-phenylglycine methyl ester and (S)-α-phenylglycine methyl ester,with preference given to chiral aralkylamine and more preference givento chiral 1-phenylethylamine.

By appropriately selecting the chiral amine, a compound [V] or anenantiomer of compound [V] can be obtained.

Suitable solvents to be used for the reaction include, for example,alcohol solvents such as methanol, ethanol, n-propyl alcohol, isopropylalcohol, n-butyl alcohol and t-butyl alcohol; hydrocarbon solvents suchas benzene, toluene, hexane and xylene; ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred are alcohol solvents and more preferred is isopropylalcohol.

The reaction temperature is suitably 0-150° C. and preferably 50-100° C.The reaction time is preferably 20 to 30 hours.

Suitable solvents to be used for crystallization include, for example,alcohol solvents such as methanol, ethanol, n-propyl alcohol, isopropylalcohol, n-butyl alcohol and t-butyl alcohol; hydrocarbon solvents suchas benzene, toluene, hexane, heptane, methylcyclohexane and xylene;ether solvents such as diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran and diglyme; halogen solvents such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solventssuch as ethyl acetate, methyl acetate and butyl acetate; polar solventssuch as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetoneand water; and mixed solvents thereof. Preferred are hydrocarbonsolvents and a mixed solvent of hydrocarbon solvent and alcohol solventand more preferred is a mixed solvent of hexane or heptane, andisopropyl alcohol.

Step (4): Removal of Chiral Element

This step comprises removing chiral element (R³) under suitableconditions from the compound [V] or an enantiomer thereof obtained inStep (3) to give a chiral compound [VI] or an enantiomer thereof.

The conditions of removal are appropriately determined according to thekind of chiral element. For example, when R³ is 1-phenylethyl, thechiral element can be removed by catalytic reduction in a suitablesolvent in the presence of a suitable catalyst such as palladiumhydroxide, and hydrogen source.

In this case, suitable catalyst includes, for example, palladiumcatalysts (e.g., palladium hydroxide-carbon, palladium-carbon andpalladium-alumina), platinum catalysts (e.g., platinum oxide), rhodiumcatalysts (e.g., rhodium-alumina) and ruthenium catalysts (e.g.,ruthenium-alumina). Preferred are to palladium catalysts with morepreference given to palladium hydroxide-carbon.

Examples of the hydrogen source include hydrogen gas, ammonium formate,formic acid, cyclohexadiene, and the like. Preferred is hydrogen gas.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide, formicacid, acetic acid and water; and mixed solvents thereof. Preferred arealcohol solvents, polar solvents and a mixed solvent of alcohol solventand polar solvent, and more preferred is a mixed solvent of isopropylalcohol, acetic acid and water.

The reaction temperature is suitably 0-100° C. and preferably 20-60° C.The reaction time is preferably 5 to 20 hours.

Step (5): Acylation of Amino Group

This step comprises acylation of amino group of compound [VI] or anenantiomer thereof using an acylating agent [VII] comprising a reactivecarboxylic acid derivative having R⁴ group, in a suitable solvent in thepresence of a suitable base, to give compound [VIII] or an enantiomerthereof.

Examples of R⁴ of the reactive carboxylic acid derivative having R⁴group, which is used as an acylating agent, include optionallysubstituted alkyl such as methyl, ethyl, propyl, butyl, s-butyl andt-butyl; optionally substituted aryl such as phenyl, 4-tolyl, 3-tolyl,2-tolyl, 3-acetoxy-2-methylphenyl, 3-hydroxy-2-methylphenyl, 1-naphthyland 2-naphthyl; optionally substituted heteroaryl such as 2-thienyl,3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl and 4-pyridyl;optionally substituted aralkyl such as benzyl, phenethyl,1-naphthylmethyl and 2-naphthylmethyl; optionally substitutedheteroarylalkyl such as 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl,3-furylmethyl, 2-pyridylmethyl, 3-pyridylmethyl and 4-pyridylmethyl; andthe like. Preferred are 3-acetoxy-2-methylphenyl and3-hydroxy-2-methylphenyl.

The reactive carboxylic acid derivative having R⁴ group is appropriatelyselected according to the substitution mode of the desired finalproduct, and, for example, acid halides, acid anhydrides and mixed acidanhydrides of carboxylic acid (R⁴COOH) having R⁴ group may be used.

Examples of acid halides of carboxylic acid (R⁴COOH) having R⁴ groupinclude R⁴COCl, R⁴COBr, and the like. Examples of acid anhydride include(R⁴CO)₂O, and the like. Examples of mixed acid anhydride includeR⁴COOCOt-Bu, R⁴COOCOOEt, and the like.

Examples of suitable base include organic base such as pyridine,lutidine, picoline, triethylamine, diisopropylethylamine,dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]-7-undecene) and DBN(1,5-diazabicyclo[4.3.0]-5-nonene); and inorganic base such as lithiumhydroxide, sodium hydroxide, potassium hydroxide, sodiumhydrogencarbonate, potassium hydrogencarbonate, sodium carbonate andpotassium carbonate. Preferred are inorganic bases, particularly sodiumhydrogencarbonate.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred is a heterogeneous solvent of Schotten-Baumanncomprising halogen solvent and water, and more preferred is a solventcomprising dichloromethane and water.

The reaction temperature is suitably 0-100° C. and preferably 10-40° C.The reaction time is preferably 1 to 5 hours.

The compound [VIII] can be used directly as an extracted solution in thenext step without isolation.

Step (6): Sulfonylation of Hydroxy

This step comprises introduction of a substituent Z which functions,together with an oxygen atom, as a leaving group wherein the hydroxy ofthe compound [VIII] or an enantiomer thereof is sulfonylated in asuitable solvent in the presence of a suitable base using a suitablesulfonylating agent to give a compound [IX] or an enantiomer thereof.

Examples of suitable sulfonylating agent include sulfonyl chloride suchas methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonylchloride and camphorsulfonyl chloride; sulfonic anhydride such asmethanesulfonic anhydride and trifluoromethane-sulfonic anhydride; andthe like. Preferred is sulfonyl chloride, and more preferred ismethanesulfonyl chloride.

Suitable base includes, for example, organic bases such as pyridine,lutidine, picoline, triethylamine, diisopropylethylamine,dimethylaminopyridine, DBU and DBN. Preferred are pyridine andtriethylamine with more preference given to triethylamine.

Suitable solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane and xylene; ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile and acetone; and mixed solventsthereof. Preferred are halogen solvents and more preferred isdichloromethane.

The reaction temperature is suitably −10-30° C. and preferably 0-20° C.The reaction time is preferably 1 to 10 hours.

The compound [IX] can be used directly as an extracted solution in thenext step without isolation.

Step (7): Formation of Oxazoline Ring

This step comprises treating compound [IX] or an enantiomer thereof witha suitable Lewis acid in a suitable solvent, thereby simultaneouslydeprotecting 1,3-dioxepane ring and forming oxazoline ring, to give acompound [X] or an enantiomer thereof wherein R⁵ is hydrogen atom. Afterthe reaction, the obtained compound is treated with a suitable acylatingagent in the same reaction vessel to convert hydroxy to acyl to give astabler compound [X] or an enantiomer thereof wherein R⁵ is acyl.

Examples of Lewis acid include, as mentioned above, titanium chloride,tin chloride, zinc chloride, zinc bromide, zinc iodide, magnesiumchloride, titanium alkoxide, boron bromide, boron chloride, boronfluoride, boron trifluoride-diethyl ether complex, aluminum chloride,aluminum bromide, thionyl chloride, phosphorus oxychloride, phosphoruschloride, trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyltrifluoromethanesulfonate, and the like. Preferred are thionyl chloride,tin chloride and boron trifluoride-diethyl ether complex. More preferredis boron trifluoride-diethyl ether complex,

Suitable solvent includes, for example, hydrocarbon solvents such asbenzene, toluene, hexane and xylene; ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetateand butyl acetate; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile and acetone; and mixed solventsthereof. Preferred are halogen solvents and more preferred isdichloromethane.

Examples of suitable acylating agent include acid halides such as acetylchloride, benzoyl chloride and pivaloyl chloride; acid anhydrides suchas acetic anhydride, benzoic anhydride and pivalic anhydride; and thelike. Preferred are acid anhydrides, more preferably acetic anhydride.

The reaction temperature is suitably 0-100° C. and preferably 10-40° C.The reaction time is preferably 1 to 50 hours.

The reaction is terminated by adding an aqueous solution of a suitablebase. Examples of the suitable base include inorganic bases such aslithium hydroxide, sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate and potassiumhydrogencarbonate; and organic bases such as N,N-dimethylethanolamineand N-methylmorpholine, which are selected as appropriate according tothe kind of Lewis acid to be used. For example, when borontrifluoride-diethyl ether complex is used, N-methylmorpholine ispreferably used.

The compound [X] can be used directly as a concentration residue in thenext step without isolation.

Step (8): Epoxidation

This step comprises treating compound [X] or an enantiomer thereof witha suitable base in a suitable solvent to give compound [XI] or anenantiomer thereof.

Suitable base includes, for example, inorganic bases such as sodiumhydride, potassium hydride, lithium hydride, lithium hydroxide, sodiumhydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogencarbonate andcalcium carbonate; and organic bases such as pyridine, triethylamine,diisopropyl ethylamine, lutidine, DBU, DBN, alkoxides (e.g., sodiummethoxide, sodium ethoxide and potassium t-butoxide), and alkali metalamides (e.g., lithium amide, sodium amide, potassium amide and lithiumdiisopropylamide), with preference given to inorganic bases and morepreference given to potassium hydroxide and potassium carbonate.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred is a mixed solvent of alcohol solvent and water, andmore preferred is a mixed solvent of water and isopropyl alcohol ormethanol.

The reaction temperature is suitably 0-100° C. and preferably 0-60° C.The reaction time is preferably 1 to 10 hours.

The compound [XI] can be used as an intermediate in a reaction mixturewithout isolation, and so-called one-pot reaction can be carried out inthe next step.

Step (9): Epoxy Ring Opening with Amine

This step comprises treating compound [XI] or an enantiomer thereof withamine [XII] in a suitable solvent to open epoxy ring, thereby to give acompound [XIII] or an enantiomer thereof.

As the amine, any amine can be used as long as it has at least onehydrogen atom on nitrogen, and examples thereof include ammonia,methylamine, ethylamine, propylamine, isopropylamine, aniline,anisidine, dimethylamine, diethylamine, dipropylamine, diisopropylamine,methylethylamine, methylisopropylamine, methylaniline, pyrrolidine,piperidine, decahydroisoquinoline,(3S,4aS,8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide, andthe like.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred is a mixed solvent of alcohol solvent and water, andmore preferred is a mixed solvent of water and isopropyl alcohol ormethanol.

The reaction temperature is suitably 0-100° C. and preferably 20-70° C.The reaction time is preferably 1 to 10 hours.

The compound [XIII] can be obtained all at once by reacting compound [X]which is a starting compound in the previous Step (8), compound [XII]and a suitable base.

Examples of the suitable base include inorganic bases such as sodiumhydride, potassium hydride, lithium hydride, lithium hydroxide, sodiumhydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogencarbonate andcalcium carbonate; and organic bases such as pyridine, triethylamine,diisopropyl ethylamine, lutidine, DBU, DBN, alkoxides (e.g., sodiummethoxide, sodium ethoxide and potassium t-butoxide), and alkali metalamides (e.g., lithium amide, sodium amide, potassium amide and lithiumdiisopropylamide). Preferred are inorganic bases with more preferencegiven to potassium carbonate.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcoholand t-butyl alcohol; hydrocarbon solvents such as benzene, toluene,hexane and xylene; ether solvents such as diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogen solvents suchas dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; polar solvents such as N,N-dimethylformamide,dimethyl sulfoxide, acetonitrile, acetone and water; and mixed solventsthereof. Preferred is a mixed solvent of alcohol solvent and water, andmore preferred is a mixed solvent of methanol and water.

The reaction temperature is suitably 0-100° C. and preferably 20-70° C.

Step (10): Oxazoline Ring Opening with Thiol

This step comprises reacting compound [XIII] or an enantiomer thereofwith thiol [XIV] in a suitable solvent in the presence of a base,thereby simultaneously opening oxazoline ring and thiolating to give acompound [XV] or an enantiomer thereof.

Examples of the thiol include alkylmercaptans such as methylmercaptan,ethylmercaptan, propylmercaptan, isopropylmercaptan, butylmercaptan,s-butylmercaptan and t-butylmercaptan; aralkylmercaptans such asbenzylmercaptan; arylmercaptans such as thiophenol and toluenethiol; andthe like. Preferred are to arylmercaptans, more preferably thiophenol.

Suitable base includes, for example, inorganic bases such as sodiumhydride, potassium hydride, lithium hydride, lithium hydroxide, sodiumhydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogencarbonate,potassium hydrogencarbonate and calcium carbonate; and organic basessuch as pyridine, triethylamine, diisopropyl-ethylamine, lutidine, DBU,DBN, alkoxides (e.g., sodium methoxide, sodium ethoxide and potassiumt-butoxide), and alkali metal amides (e.g., lithium amide, sodium amide,potassium amide and lithium diisopropylamide), with preference given totriethylamine and potassium hydrogencarbonate.

Suitable solvent includes, for example, alcohol solvents such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol,t-butyl alcohol and ethylene glycol; hydrocarbon solvents such asbenzene, toluene, hexane and xylene; ether solvents such as diethylether, 1,2-dimethoxyethane, tetrahydrofuran and diglyme; halogensolvents such as dichloromethane, chloroform, carbon tetrachloride and1,2-dichloroethane; polar solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and acetone;ketone solvents such as methyl isobutyl ketone, diethyl ketone andmethyl ethyl ketone; and mixed solvents thereof. Preferred are polarsolvents and ketone solvents, and more preferred areN,N-dimethylformamide and methyl isobutyl ketone.

The reaction temperature is suitably 0-150° C. and preferably 80-130° C.The reaction time is preferably 1 to 30 hours.

The enantiomers of the above-mentioned compound [XV] and variousintermediates can be obtained by the same reactions as above using anenantiomer of compound [V] obtained in Step (3).

The compound [XV], various intermediates and enantiomers thereof can beobtained at optional purity by appropriately applying separation andpurification conventionally known, such as concentration, extraction,chromatography, reprecipitation and recrystallization.

The salts of the above-mentioned compound [XV], various intermediatesand various isomers thereof can be produced by a known method.

The present invention is described in detail by way of illustrativeExamples in the following, to which the invention is not limited.

Examples are shown in a schematic flow in the following.

wherein Ph is phenyl, Ac is acetyl, Me is methyl and Bu-t is t-butyl.

REFERENCE EXAMPLE 1 3-Acetoxy-2-methyl benzoic acid

3-Nitro-2-methyl benzoic acid (90.5 g, 0.500 mol) was dissolved in 1.0mol/L aqueous solution (500 ml) of sodium hydroxide. 10%Palladium-carbon (4.5 g) was added and the mixture was stirred under ahydrogen atmosphere (2-3 atm) for 9 hours at 40° C. The catalyst wasfiltered off and conc. sulfuric acid (94.0 ml) was added underice-cooling. An aqueous solution of sodium nitrite (35.0 g, 0.500mol/150 ml) was added over one hour while stirring the mixture at notmore than 6° C., and after the dropwise addition, the mixture was heatedat 65° C. for 1.5 hours. The inner temperature rose to 57° C. in anhour. The reaction mixture was cooled to room temperature, and saturatedbrine (300 ml) was added. The mixture was extracted with ethyl acetate(700 ml). The organic layer was washed with saturated brine (200 ml) anddried over magnesium sulfate. The solvent was distilled away to give3-hydroxy-2-methyl benzoic acid as a pale brown solid.

This substance was dissolved in pyridine (500 ml), and acetic anhydride(100 ml) was added at room temperature, which was followed by stirringat room temperature for 3.5 hours. Ethanol (100 ml) which was kept atnot more than 10° C. was added to the reaction mixture, and the mixturewas stirred for another hour at room temperature. The mixture wasconcentrated to give a brown oil. The oil was dissolved in ethyl acetate(800 ml) and washed successively with 1N hydrochloric acid (500 ml) andsaturated brine (300 ml). Magnesium sulfate and active charcoal (4.00 g)were added to the organic layer, and the mixture was stirred for 30minutes. The insoluble matter was filtered off and the filtrate wasconcentrated to dryness. Acetic acid in this product was removed byazeotropy using toluene (400 ml), and the residue was washed withtoluene (450 ml) to give 3-acetoxy-2-methyl benzoic acid (70.1 g, yield72%) as colorless crystals, melting point 146-148° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 7.95 (dd,1H,J=1.5,7.3 Hz), 7.30 (t,1H, J=7.7Hz), 7.24 (dd,1H,J=1.5,8.1 Hz), 2.46 (s,3H), 2.36 (s,3H)

IR (KBr): 2984, 2816, 1766, 1687, 1460, 1311, 1279, 1211, 1039, 930,766, 752 cm⁻¹

Elemental Analysis (C₁₀H₁₀O₄): Calculated: C,61.85;H,5.19. Found:C,61.91;H,4.94.

EXAMPLE 1 Production of Compound [2] (Step 1)

To a mixture of (z)-2-butene-1,4-diol (compound [1], 211.4 g, 2.4 mol)and 2,2-dimethoxypropane (590.2 ml, 4.8 mol) was added p-toluenesulfonicacid monohydrate (30 mg). The solution thus obtained was evaporatedunder atmospheric pressure to give a colorless transparent liquid of2,2-dimethyl-4,7-dihydro-1,3-dioxepine (compound [2], 245 g, yield 80%),boiling point 140-145° C./760 mmHg.

¹H-NMR (CDCl₃, 300 MHz) δ: 5.67 (diffused s,2H), 4.26 (diffused s, 4H),1.44 (s,6H)

EXAMPLE 2 Production of Compound [3] (Step 2)

2,2-Dimethyl-4,7-dihydro-1,3-dioxepine (compound [2], 94.0 g, 0.734mol), methanol (220 ml) and acetonitrile (116 ml, 2.20 mol) were mixedand the mixture was heated to 60° C. A 30% aqueous hydrogen peroxidesolution (208 ml, 1.84 mol) was dropwise added over 1.5 hours at 60-70°C. Simultaneously, an aqueous solution of 1M sodium hydroxide wasdropwise added to adjust the reaction system to a pH of 9.1-9.6. Evenafter the dropwise addition of the aqueous solution of hydrogenperoxide, the dropwise addition of the aqueous solution of 1M sodiumhydroxide was continued, during which time the pH was kept at 9.1-9.6and temperature at 50-70° C., and the mixture was stirred for 1.5 hours.The reaction mixture was cooled to room temperature, diluted withsaturated brine (220 ml) and extracted with chloroform (180 ml×1, 90ml×2). The organic layers were combined, washed with an aqueous solutionof sodium hydrogensulfite (300 ml, 15 g) and dried over magnesiumsulfate. The solvent was evaporated and the residue was distilled togive a colorless, transparent liquid of4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (compound [3], 86.7 g,yield 82%), boiling point 70-74° C./17 mmHg.

¹H-NMR (CDCl₃, 300 MHz) δ: 4.08-3.97 (m,4H), 3.22-3.18 (m,2H), 1.37(s,3H), 1.32 (s,3H)

EXAMPLE 3 Production of Compound [5] (Step 3)

4,4-Dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (compound [3], 142 g,0.988 mol) obtained above and (R)-1-phenylethylamine (compound [4], 120g, 0.988 mol) were dissolved in isopropyl alcohol (400 ml). The mixturewas refluxed under heating for 24 hours and concentrated to 366 g.Hexane (400 ml) was added to the residue and the mixture was stirred at5° C. for one hour. The precipitated crystals were collected byfiltration, washed with hexane and dried to give colorless crystals of(5R,6S)-2,2-dimethyl-6-[(R)-1-phenylethylamino]-1,3-dioxepan-5-ol(compound [5], 94.0 g, yield 36%), melting point 108-108.5° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 7.33-7.22 (m,5H), 3.95 (q,1H,J=6.5 Hz), 3.75(dd,1H,J=1.8,12.1 Hz), 3.74 (dd,1H,J=2.0,12.5 Hz), 3.52 (dd,1H,J=5.5,12.5 Hz), 3.48 (ddd,1H,J=0.5,5.9,12.1 Hz), 3.37 (dt,1H, J=1.4,5.6Hz), 2.44 (br s,1H), 2.34 (dt,1H,J=1.7,5.5 Hz), 1.34 (d,3H, J=6.5 Hz),1.34 (s,3H), 1.31 (s,3H)

IR (KBr): 3406, 2590, 1452, 1374, 1219, 1072, 1052, 841, 758, 696 cm³¹ ¹

[α]_(D) ²⁵: +91.0° (c1.00, MeOH)

Elemental Analysis (C₁₅H₂₃NO₃): Calculated: C,67.90;H,8.74;N,5.28.Found: C,67.90;H,9.01;N,5.31.

EXAMPLE 4 Production of Compound [6] (Step 4)

20% Palladium hydroxide-carbon (50% wet type, 9.20 g) was suspended inisopropyl alcohol (550 ml), and(5R,6S)-2,2-dimethyl-6-[(R)-1-phenylethylamino]-1,3-dioxepan-5-ol(compound [5], 92.0 g, 37.7 mmol) and acetic acid (20.8 ml, 37.7 mmol)were added. The mixture was stirred at room temperature under hydrogenatmosphere (3.0 atm) for 8 hours. The catalyst was removed by Celitefiltration and the filtrate was concentrated to 105 g. Hexane (400 ml)was added to the residue and the obtained suspension was stirred toallow precipitation of thin crystals. The crystals were collected byfiltration and dried to give colorless crystals of(5R,6S)-6-amino-2,2-dimethyl-1,3-dioxepan-5-ol acetate (compound [6],76.6 g, yield 100%), melting point 133-134° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 3.84 (dd,1H,J=2.5,12.7 Hz), 3.74 (dd,1H,J=2.5,12.5 Hz), 3.67-3.53 (m,3H), 2.98 (dt,J=2.4,6.5 Hz), 1.91 (s,3H),1.33 (s,6H)

IR (KBr):3178, 2993, 1617, 1561, 1525, 1409, 1385, 1223, 1087, 1031, 846cm³¹ ¹

[α]_(D) ²⁵: +29.6° (c1.05, MeOH)

Elemental Analysis (C₉H₁₉NO₅): Calculated: C,48.86;H,8.66;N,6.33. Found:C,48.98;H,8.70;N,6.36.

EXAMPLE 5 Production of Compound [8] (Step 5)

Sodium hydrogencarbonate (42.0 g, 0.500 mol) was suspended in water (350ml) and (5R,6S)-6-amino-2,2-dimethyl-1,3-dioxepan-5-ol acetate (compound[6], 44.3 g, 0.200 mol) was added. Then, a solution of3-acetoxy-2-methylbenzoyl chloride (43.0 g, 0.200 mol) which can beeasily obtained from the aforementioned 3-acetoxy-2-methyl benzoic acidby a known method, in ethyl acetate (650 ml) was added at roomtemperature. The mixture was stirred at room temperature for 12 hoursand saturated brine (200 ml) was added. The organic layer was separated,washed with saturated brine (300 ml) and dried over magnesium sulfate.The solvent was distilled away to give a colorless solid of(5R,6S)-N-(2,2-dimethyl-5-hydroxy-1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide(compound [8], 76.0 g, yield 113%), melting point 93-94° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 7.28-7.22 (m,2H), 7.10 (m,1H), 6.39(d,1H,J=7.9 Hz), 4.15-4.07 (m,2H), 3.83-3.78 (m,2H), 3.63 (ddd,1H,J=1.5,3.8,12.7 Hz), 3.55 (ddd,1H,J=1.1,3.4,12.7 Hz), 2.98 (br s,1H),2.34 (s,3H), 2.24 (s,3H), 1.37 (s,3H), 1.33 (s,3H)

IR (KBr): 3305, 2947, 1760, 1638, 1534, 1374, 1218, 1177, 1054, 844 cm⁻¹

[α]_(D) ²⁵: +35.2° (c1.34, MeOH)

Elemental Analysis (C₁₇H₂₃NO₆): Calculated: C,60.52;H,6.87;N,4.15.Found: C,60.88;H,6.92;N,4.02.

EXAMPLE 6 Production of Compound [9] (Step 6)

(5R,6S)-N-(2,2-Dimethyl-5-hydroxy-1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide(compound [8], 44.3 g, 0.200 mol) was dissolved in dichloromethane (800ml), and triethylamine (36.2 ml, 0.260 mol) and methanesulfonyl chloride(18.6 ml, 0.240 mol) were added under ice-cooling. The mixture wasstirred for one hour at room temperature. A saturated solution (600 ml)of sodium hydrogencarbonate was added under ice-cooling, and the organiclayer was separated, washed successively with a 10% aqueous solution(500 ml) of citric acid and saturated brine (500 ml) and dried overmagnesium sulfate. The solvent was distilled away under reducedpressure, and toluene (700 ml) was added to the residue to allowprecipitation of crystals. The crystals were collected by filtrationunder reduced pressure and dried to give colorless crystals of(5R,6S)-N-(5-methanesulfonyloxy-2,2-dimethyl-1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide(compound [9], 75.9 g, yield 91%), melting point 127-128° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 7.30-7.25 (m,2H), 7.13 (m, 1H), 6.50(d,1H,J=7.3 Hz), 4.65 (m,1H), 4.22-4.18 (m,2H), 3.96 (ddd,1H,j=1.3,3.1,14.1 Hz), 3.88 (dd,1H,J=1.2,14.0 Hz), 3.60 (ddd, 1H,J=1.2,3.6,12.9 Hz), 3.24 (s,3H), 2.35 (s,3H), 2.25 (s,3H), 1.39 (s,3H),1.34 (s,3H)

IR (KBr): 3348, 2941, 1763, 1654, 1639, 1540, 1340, 1207, 1174, 1085,939, 825 cm⁻¹

[α]_(D) ²⁵: +73.9° (c1.22, CHCl₃)

Elemental Analysis (C₁₈H₂₅NO₈S): Calculated: C,52.04;H,6.07;N,3.37.Found: C,52.20;H,6.12;N,3.42.

EXAMPLE 7 Production of Compound [10] (Step 7)

(5R,6S)-N-(5-Methanesulfonyloxy-2,2-dimethyl1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide(compound [9], 34.2 g, 82.3 mmol) was dissolved in dichloromethane (340ml) and boron trifluoride-diethyl ether complex (30.4 ml, 247 mmol) wasadded over 5 minutes with stirring at room temperature. The mixture wasstirred for 40 hours at room temperature. Triethylamine (34.5 ml, 247mmol) was added at not more than 15° C. and the solvent was distilledaway under reduced pressure to 1/5 volume. The residue was diluted withethyl acetate (340 ml) and washed successively with 10% brine (340 ml),10% brine (340 ml) containing citric acid (17 g), and saturated brine(340 ml). After drying over magnesium sulfate, the solution wasconcentrated to 36 g to give a crude product of(2R)-2-methanesulfonyloxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)ethanol(compound [10]).

EXAMPLE 8 Production of Compound [11] (Step 8)

The crude product of compound [10] was suspended in isopropyl alcohol(340 ml) and cooled in an ice bath. An aqueous solution of potassiumhydroxide (14.6 g, 260 mmol/68 ml) was added to the suspension at notmore than 10° C. and the mixture was stirred at 5° C. for 2.5 hours togive a suspension containing pale yellow(2S)-2-((4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)oxirane(compound [11]).

EXAMPLE 9 Production of Compound [13] (Step 9)

Acetic acid (14.0 ml, 245 mmol) was added to the mixture obtained inExample 8 at not more than 10° C. to make the mixture acidic, andpotassium hydrogencarbonate (25.0 g, 250 mmol) and(3S,4aS,8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide(compound [12], 13.7 g, 57.6 mmol) were successively added. The mixturewas stirred at 45° C. for 6 hours to give a pale yellow suspension. Thesuspension was concentrated to 1/5 and water (340 ml) was added. Thesuspension was stirred for one hour at room temperature. The resultingcrystals were collected by filtration and washed successively with water(200 ml) and butyl acetate (340 ml). The crystals were dried underreduced pressure at 60° C. to give colorless crystals of(3S,4aS,8aS)-2-{(2R)-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylicacid t-butylamide (compound [13], 17.3 g, yield 46%, from compound [9]),melting point 240° C.

¹H-NMR (D₆-DMSO, 300 MHz) δ: 9.48 (br.s,1H), 7.36 (s,1H), 7.08(dd,1H,J=1.5,7.7 Hz), 7.02 (t,1H,J=7.7 Hz), 6.89 (dd,1H,J=1.4,7.7 Hz),4.74 (d,1H,J=5.4 Hz), 4.46 (m,1H), 4.28 (dd,1H,J=8.1,9.9 Hz), 4.15(t,1H,J=8.1 Hz), 3.75 (m,1H), 2.91 (br.d,1H,J=10.3 Hz), 2.58 (dd,1H,J=2.6,11.0 Hz), 2.36 (dd,1H,J=8.8,12.8 Hz), 2.28 (s,3H), 2.12-2.03(m,2H), 1.99-1.81 (m,2H), 1.60-1.54 (m,2H), 1.56-1.48 (m,3H), 1.32-1.19(m,5H), 1.24 (s,9H)

IR (KBr): 3238, 2928, 1645, 1624, 1578, 1560, 1460, 1362, 1279, 1128,1048 cm⁻¹

[α]_(D) ²⁵: −47.3° (c1.02, DMF)

Elemental Analysis (C₂₆H₃₉N₃O₄) Calculated: C,68.24;H,8.59;N,9.18.Found: C,68.30;H,8.83;N,9.06.

EXAMPLE 10 Production of Compound [15] (Step 10)

(3S,4aS,8aS)-2-{(2R)-2-[(4S)-2-(3-Hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylicacid t-butylamide (compound [13], 16.9 g, 37.0 mmol) was suspended inpyridine (170 ml) and thiophenol (15.2 ml, 148 mmol) was added at roomtemperature. The mixture was stirred at 80° C. for 13 hours. The mixturewas cooled to room temperature and active charcoal (1.70 g) was added.The mixture was stirred at room temperature for 30 minutes andunnecessary matter was removed using Celite. The filtrate wasconcentrated and the residual pyridine was removed by azeotropy with2-butanone (150 ml). 2-Butanone (200 ml) was added to the residue andthe mixture was refluxed for 2 hours with stirring, during whichprocedure colorless crystals precipitated. The mixture was left-standingat −15° C. for 40 hours and the resulting crystals were collected byfiltration. The crystals were washed with a 2-butanol:toluene (1:1)solution (150 ml) and dried in vacuo at 50° C. to give colorlesscrystals of(3S,4aS,8aS)-2-[(2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl]decahydroiso-quinoline-3-carboxylicacid t-butylamide (compound [15], 14.4 g, yield 69%).

EXAMPLE 11 Production of Compound [10′] (Step 7′)

(5R,6S)-N-(5-Methanesulfonyloxy-2,2-dimethyl-1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide(compound [9], 786 g, 1.89 mol) was dissolved in dichloromethane (6.29L), and boron trifluoride diethyl ether (698 ml, 5.68 mol) was added,which was followed by stirring at room temperature for 23 hours. Thereaction mixture was cooled to 11° C. and acetic anhydride (268 ml, 2.84mol) was added, which was followed by stirring at said temperature for 2hours. The reaction mixture was concentrated to 2.0 kg under reducedpressure and toluene (3.8 L) was added to the obtained residue to give asuspension. N,N-Dimethylethanolamine (571 ml, 5.68 mol) was added to thesuspension over 40 minutes at not more than 20° C. Toluene (1.5 L) andwater (4.8 L) were added and the mixture was stirred for one hour atroom temperature. The organic layer was separated, washed successivelywith a 10% aqueous citric acid solution (5.00 L) and a 2% aqueouspotassium carbonate solution (5.00 L) and dried over magnesium sulfate.The desiccant was filtered off and the filtrate was concentrated underreduced pressure to give(2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2-methanesulfonyloxyethane(compound [10′], 1.04 kg) as a dark red oil.

¹H-NMR (CDCl₃, 300 MHz) δ: 7.68 (d,1H,J=7.7 Hz), 7.26 (t,1H,J=7.9 Hz),7.14 (d,1H,J=8.0 Hz), 5.02 (dt,1H,J=7.7,3.7 Hz), 4.66 (ddd,1H,J=3.6,8.1,9.5 Hz), 4.53 (dd,1H,J=3.3,12.4 Hz), 4.47-4.38 (m,3H), 3.11(s,3H), 2.40 (s,3H), 2.34 (s,3H), 2.10 (2,3H)

EXAMPLE 12 Production of Compound [13](Step 8′)

The unpurified(2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methyl-phenyl)-4,5-dihydrooxazol-4-yl)-2-methanesulfonyloxyethane(compound [10′], 1.04 kg, 1.89 mol) obtained in Example 11 was suspendedin isopropyl alcohol (4.8 L) and an aqueous potassium hydroxide solution(531 g/1.6 L, 9.46 mol) was dropwise added over 45 minutes at not morethan 18° C., which was followed by stirring for one hour at 10° C.Acetic acid (325 ml, 5.68 mol) was added at not more than 10° C. toneutralize the mixture, and potassium hydrogencarbonate (568 g, 5.68mol) and (3S,4aS,8aS)-decahydroisoquinoline-3-carboxylic acidt-butylamide (compound [12], 361 g, 1.51 mol) were successively added.The mixture was stirred at 40° C. for 6 hours and the resulting crystalswere collected by filtration. The crystals were suspended in water (5.5L) and the suspension was stirred for 30 minutes. The crystals wereagain collected by filtration, washed with water (2.5 L) and butylacetate (4.00 L), and dried under reduced pressure at 60° C. to give(3S,4aS,8aS)-2-{(2R)-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylicacid t-butylamide (compound [13], 443 g, yield 51%, from compound [9])as colorless crystals.

EXAMPLE 13 Production of Compound [15] (Step 10′)

(3S,4aS,8aS)-2-{(2R)-2-[(4S)-2-(3-Hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylicacid t-butylamide (compound [13], 410.5 g, 0.897 mol) was suspended inN,N-dimethylformamide (2.47 L), and triethylamine (1.00 L, 7.18 mol) andthiophenol (368 ml, 3.59 mol) were added, which was followed by stirringat 75° C. for 10 hours. The mixture was cooled to room temperature andthe reaction mixture was dropwise added into water (7.5 L) over 30minutes. The resulting crystals were collected by filtration andresuspended in toluene (7.00 L), which was followed by stirring for 30minutes. The crystals were again collected by filtration and dried at60° C. for 34 hours under reduced pressure. The crude crystals weresuspended in methyl ethyl ketone (10.0 L) and refluxed under heating togive a solution, which was left standing at room temperature for 16hours to allow recrystallization. The crystals were collected byfiltration, washed with methyl ethyl ketone (1.00 L) and dried at 60° C.for 6 hours under reduced pressure to give(3S,4aS,8aS)-2-[(2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylicacid t-butylamide (compound [15], 330.1 g, yield 65%) as colorlesscrystals.

EXAMPLE 14 Production of Compound [13] (Step 8′)

The crude product of(2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2-methanesulfonyloxyethane(compound [10′], 1.98 kg, 3.30 mol) obtained in Example 11 was suspendedin a mixed solvent of methanol (6.50 L) and water (6.50 L), and(3S,4aS,8aS)-decahydroisoquinoline-3-carboxylic acid t-butylamide(compound [12], 642 g, 2.62 mol) and potassium carbonate (1.36 kg, 9.81mol) were successively added, which was followed by stirring at 50° C.for 5.5 hours. Water (6.50 L) was added to cool the reaction mixture toroom temperature and the resulting crystals were collected byfiltration. These crude crystals were again suspended in water (6.50 L),stirred, washed and collected by filtration. The obtained crystals werere-suspended in methyl isobutyl ketone (10.0 L) and the suspension wassubjected to azeotropic dehydration. The obtained residue was cooled toroom temperature and crystals were collected by filtration to give (3S,4aS,8aS)-2-{(2R)-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylicacid t-butylamide (compound [13], 902 g, 1.97 mol, yield 60%, fromcompound [6]) as colorless crystals.

EXAMPLE 15 Production of Compound [15] (Step 10′)

(3S,4aS,8aS)-2-{(2R)-2-[(4S)-2-(3-Hydroxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl]-2-hydroxyethyl}decahydroisoquinoline-3-carboxylicacid t-butylamide (compound [13], 701 g, 1.53 mol) was suspended inmethyl isobutyl ketone (7.00 L), and thiophenol (314 ml, 3.06 mol) andpotassium hydrogencarbonate (76.6 g, 0.765 mol) were added. The mixturewas refluxed under heating for 12 hours under a nitrogen stream. Afterthe completion of the reaction, toluene (7.00 L) was added, and theprecipitated crystals were collected by filtration and washed withtoluene. These crude crystals were washed with heating in a mixedsolvent of acetone and water (1:1) to give(3S,4aS,8aS)-2-[(2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylicacid t-butylamide (compound [15], 695 g, 1.22 mol, yield 80%) ascolorless crystals.

The production method of the present invention is extremely easy andsimple as compared to the conventional methods, and enables effectiveproduction of compound [XV] at high yields, which includes compound[XVI] having an HIV protease inhibitory action. In addition, the novelintermediates of the present invention are extremely useful asintermediates for producing not only the aforementioned compound [XVI]but also compounds useful as X-ray contrast media such as the compoundsfor X-ray image development as described in U.S. Pat. No. 4,439,613.

What is claimed is:
 1. An (oxazolin-4-yl)oxirane derivative of theformula [XI]

wherein R⁴ is an optionally substituted alkyl, an optionally substitutedaryl, an optionally substituted heteroaryl, an optionally substitutedaralkyl or an optionally substituted heteroarylalkyl, an enantiomerthereof or a salt thereof.
 2. A method for producing an(oxazolin-4-yl)oxirane derivative of the formula [XI]

wherein R⁴ is an optionally substituted alkyl, an optionally substitutedaryl, an optionally substituted heteroaryl, an optionally substitutedaralkyl or an optionally substituted heteroarylalkyl, or an enantiomerthereof, comprising treating an oxazoline derivative of the formula [X]

wherein R⁴ is as defined above, R⁵ is a hydrogen atom or an acyl, and Zis a substituent which functions as a leaving group together with anoxygen atom, or an enantiomer thereof, with a base.
 3. A method forproducing an (oxazolin-4-yl)oxirane derivative of the formula [XI]

wherein R⁴ is an optionally substituted alkyl, an optionally substitutedaryl, an optionally substituted heteroaryl, an optionally substitutedaralkyl or an optionally substituted heteroarylalkyl, or an enantiomerthereof, comprising reacting a (5R,6S)-6-amino-1,3-dioxepan-5-olderivative of the formula [VI]

wherein R¹ and R² are the same or different and each is a hydrogen atom,an alkyl or an aryl, or R¹ and R² combinedly form a cycloalkyl ringtogether with the adjacent carbon atom, an enantiomer thereof or a saltthereof, with a reactive carboxylic acid derivative having R⁴ wherein R⁴is as defined above, in the presence of a base, to give a(5R,6S)-6-acylamino-1,3-dioxepan-5-ol derivative of the formula [VIII]

wherein R¹, R² and R⁴ are as defined above, or an enantiomer thereof,reacting the resulting compound with a sulfonylating agent, treatingwith a Lewis acid, acylating, where necessary, to give an oxazolinederivative of the formula [X]

wherein R⁴ is as defined above, R⁵ is a hydrogen atom or an acyl, and Zis a substituent which functions as a leaving group together with anoxygen atom, or an enantiomer thereof, and treating the obtainedcompound with a base.